Alpha-amino-omega-aralkylimino penicillanic acids

ABSTRACT

New 6-( Alpha -(amino)aralkylideneimino)penicillanic acid broad spectrum antibiotics and derivatives and salts thereof.

United States Patent Butler Aug. 5, 1975 [54}ALPHA-AMINO-OMEGA-ARALKYLIMINO 3,479 4Ul 1 1/1969 Putchett et Lll260/2391 PENlClLLANlC ACIDS [75] Inventor: Kenneth Butler, Old LymeConn.

Primary EA'CUHHZCf-NICI'IOIHS S. R1220 Asslgneei Pfizer -v New YorkAttorney, Agent, or Firm-C0nnol]y and Hutz [22] Filed: May 25. I971Appl. No.: 146,786

U.S. Cl 260/306.7 C; 260/239]; 424/27] Int. Cl l. C07d 99/10 Field ofSearch 260/2391 References Cited UNITED STATES PATENTS 7/1969 Putchettet ul l. 260/2391 5 7] ABSTRACT 11 Claims, No DrawingsALPHA-AMINO-()MEGA-ARALKYLIMINO PENICILLANIC ACIDS BACKGROUND OF THEINVENTION The pharmacodynamic and antibiotic properties of a givenpenicillin are determined to a great extent by the nature of the Rgroup. The most widely used penicillins are those wherein the R moietyis represented by benzyl. phenoxymethyland 01-phcnoxyethyl-. While thesewell-known analogs are highly aantagonistic toward gram-positivemicro-organisms they have limited gram-negative activity. Consequently,drugs which will combat rise in gram-negative infections, e.g.. E. cull.are of value to the medical profession.

Recent efforts to improve the profile of activity within the family ofpenicillins has resulted in the synthesis of wearboxybenzylpenicillin(US. Pat. No. 3.l42.673 a broad spectrum antibiotic with greaterefficacy against gram-negative infections via the parenteral route ofadministration. More recently, broad spectrum activity has been claimedfor a series of (Pla-(guanyl)thienylacetamidelpenicillanic acids inBritish Patent l,l64,457 and for a series of 6-[01-guanylureido)phenylacetamide lpenicillanic acids. Belgium Specification742.423.

Ar- (CH -CONH SUMMARY OF THE INVENTION The novel antibacterial 6-[ a-(amino )aralkylideneiminolpenicillanic acids of the instant invention arerepresented by the formula:

I cs 3 Ar (cs c N\ s CH r-u o c0 11 where:

Ar is phenyl. furyl or thicnyl; n is an integer of from 0 to 2; R, and Rwhen considered separately are each s 3 Er fog 5 2- R R NH N 1 2 COZR3alkyl containing 1 to 5 carbon atoms; R, and R when taken together withthe nitrogen atom to which they are attached form a heterocyclic ring ofthe formula:

wherein and y are integers of from I to 3; and Z is CH O, S. or N- 1'1,wherein R, is selected from the group consisting of hydrogen. benzoyl.phenyl, alkyl containing l to 4 carbon atoms, alkanoyl and alkylsulfonyl each containing 1 to 4 carbon atoms and carboalkoxy containingfrom 2 to 5 carbon atoms; R is hydrogen. alkyl containing 1 to 4 carbonatoms, phenacyl or l-alkanoyloxyalkyl where said alkanoyl contains 2 to5 carbon atoms and said alkyl contains l to 4 carbon atoms;pharmaceutically acceptable acid addition salts thereof; andpharmaceutically acceptable basic salts wherein R is hydrogen.

A preferred group of congeners are those wherein Ar is phenyl. n is l.R, and R are each alkyl containing from 1 t0 5 Carbon atoms and R iseither hydrogen or l-alkanoyloxyalkyl where said alkanoyl contains from2 to 5 carbon atoms and said alkyl contains from 1 to 4 carbon atoms.

A second preferred group of compounds are those wherein Ar is phenyl, nis l. R, and R when taken together with the nitrogen to which they areattached form a morpholino or N-methyl piperidino ring and R is eitherphenacyl or l-alkanoyloxyalkyl where said alkanoyl contains from 2 to 5carbon atoms and said alkyl contains from l to 4 carbon atoms.

Also within the scope of the instant invention are congeners wherein R,is alkyl and R is hydrogen or alkyl and wherein R, and R taken togetherare N-phenylpiperazine wherein the phenyl moiety is substituted bysimple substituents usually found on benzene rings, cg, alkyl. alkoxy.halo, etc.

DETAILED DESCRIPTION OF THE INVENTION The novel and valuable compoundsof the present invention are prepared from the corresponding penicillinesters as illustrated:

wherein Ar. n. R, and R are as previously indicated, and R is alkyl.phenacyl or l-alkanoyloxyalkyl.

Treatment of compounds of formula I with phosphorous pentachloridcresults in the formation of the corresponding imino chloride. Treatmentof this product with the secondary amine, R,R NH, provides thepreparation of the final products of the instant invention. asillustrated abovev In practice. a solution of the appropriate penicillinester in an aprotic solvent. e.g.. chloroform or methylcne chloride. andcooled to (l-5 C.. is treated with at least an equimolar amount ofphosphorous pentachlo ride and approximately four equivalents ofpyridine. The described reaction is facile and requires l53() minutes atice-bath temperatures. It is advantageous. because of the labilily ofiininochlorides. to use the product without isolation or purification.Following this procedure. the solution of the product is washed withwater. dried over sodium sulfate and treated. in the cold. with therequiside secondary amine. At least two molar equivalents of amine areemployed. plus as much as a It) percent excess. The reaction iscompleted in 30-90 minutes at ice-bath temperatures. and the product isisolated by addition of water and subsequent extraction of the product,as the hydrochloride salt. into the water-immiscible reaction solvent.

The acid addition salts of the products of the instant inventionrepresent compounds of varying degrees of lipophylicity and consequentlyvarying degrees of solubility in aqueous and nonaqueous solvents. As oneskilled in the art appreciates, as the lipophylicity of the productsincreases the acid addition salts thereof dis play a dimished solubilityin water or aqueous systems in favor of organic solvent systems. whilethe converse is true as lipophilicity decreases. In those instanceswherein the salt of the product has greater solubility in the aqueousphase. said aqueous solution is made alkaline using a sodium hydroxidesolution and the product as the free base extracted into an appropriatewaterimmiscible solvent such as benzene. methylene chloride orchloroform.

Compounds of the present invention of formula ll wherein R is hydrogenare prepared from the corre' sponding phenaeyl esters using an exchangereaction employing thiophenoxidc ion as the nucleophile:

Experimentally, a solution of the requisite phenacyl ester in a highlypolar solvent such as dimethylformamide or hexamethylphosphoramidc istreated with an equimolar quantity of sodium thiophenoxid. At ambi enttemperatures the reaction is comple e in 304m minutes and the product isisolated by ilution with a non-polar solvent such as diethyl ether. Theprecipitated sodium salt is washed free of reaction solvent usingadditional quantities of ether.

The starting reagents leading to the products of the present inventionare easily prcparcd by methods known to those skilled in the art. Thepenicillin esters are prepared from the corresponding pcnicillins via alkylation of the carboxyl group as taught by Jansen. ct. al..J. (7mm.Soc. 3733 H953) and 2127 I965), Penicillins are conveniently formedthrough the acylation of o-aminopenicillanic acid with the requisiteacid halilc or acid in the presence of N.l\l"dicyclohexylcarbodiimide astaught by Doyle. ct al.. .7. (7mm. Soc. 1453 N962) and Hobbs. et al. .1.Alert. ('/1('m.. 4. 207 (1961). respectively. The l-alkanoyloxyalkylhalides employed for the alkylation of the atorcmentioncd pct:- icillinsare either commercially available or can be synthesized according to thegeneral procedure of Ulich. et al., J. Am. Chem. Soc; 43. Mill (i921)and Euranto. et. al.. Arm. (72cm. Scum/ 30. I273 won As has beenpreviously noted. a characteristic feature of the acidic compounds ofthe instant invention. i.e.. wherein R is hydrogen. is their ability toform basic salts. Acid congencrs of the present invention are convertedto basic salts by the interaction of said acid with an appropriate basein an aqueous or nonaqueous me dium. Such basic reagents suitablyemployed in the preparation of said salts can vary in nature. and aremeant to contemplate such bases as organic amines. ammonia. alkali metalhydroxides. carbonates. bicarbonates. hydrides and alkoxides. as well asalkali earth metal hydroxides. hydrides. alkoxides and carbonates.Representative of such bases are ammonia. primary amines such asn-propylamine. n-butylamine. aniline. cyclohexylamine. benzylamine.p-toluidine. ethylamine. octylamine. secondary amines such asdicyclohexylamine and tertiary amines such as dietliylaniline. N-methylpyrrolidine. Nmethylmorpholine and l.5-diazabicyclo-[4.3.Ul-5-nonene; sodium hydroxide. potassium hydroxide.ammonium hydroxide. sodium ethoxide. potassium methoxidc. magnesiumhydroxide. calcium hydride and barium hydroxide.

in the utilization of the chemotherapeutic activity of those compoundsof the present invention which form basic salts. it is preferred. ofcourse. to use pharmaceu tic-ally acceptable salts. Although waterinsolubility. high toxicity. or lack of crystalline nature may make somesalt species unsuitable or less desirable for use as such in a givenpharmaceutical application. the water insoluble or toxic salts can bcconverted to the corresponding acids by decomposition of the salts asdcscribcd above. or alternately they can be converted to any desiredpharmaccutically acceptable basic salt. The said pharmaceuticallyacceptable salts preferred include the sodium aluminum. potassium.calcium. magnesium. ammonium and substituted ammonium salts. cg.procaine. dibenxylamine. N N dibenzylethylcncdiarninc. NN-bisldehydroabictyl )ethylenediaminc. Lephcnaminc. N-ethylpiperidine.

N-ben2yl-B-phenethylamine. tricthylaniinc. as well as salts with otheramines which have been used to form salts with bcnzylpenicillin.

As has been previously mentioned. the basic compounds of the presentinvention can be converted to the acid addition salts by interaction ofthe base with an acid either in an aqueous or nonaqueous medium. In asimilar manner. treatment of the acid addition salts with an equivalentamount of an aqueous base solution. e.g.. alkali metal hydroxides.alkali metal carbonates and alkali metal bicarbonatcs or with .121equivalent amount of a metal cation which forms an insoluble prccipitatc with the acid anion. results in a regeneration of the free baseform. Such conversions art: best carried out as rapidly as possible andunder temperature conditions and method dictated by the -tability ofsaid basic products. The bases thus regenerated may be recov crcd to thesame or a different acid addition salt.

i l the utilization ofthc chcnnitlicrapeutic activity of those compoundsof the present invention which form salts. it is preferred. of course.to use pharmaceutically acceptable salts. Although water insolubility.high too icity. or lack ofcrystallinc nature ma make some particularsalt spccici unsuitablc til less dcsirablc for use as such in a givenpharmaceutical application. the water insoluble or toxic salts can beconvertet'l to the corresponding pharmaccutically acceptable bases bydecomposition ot the salt as described above, or alter tilely they canbe converted to any desired pharmaceutically acceptable acid additionsalt.

Examples of acids which provide pharmaceutically acceptable anions arehydrochloric, hydrobromic. hydroiodic, nitric, sulfuric, or sulfurous,phosphoric, acetic. lactic, citric, tartaric, succinie. maleic, andgluconic acids.

The novel penicillins described herein exhibit in vitro activity againsta wide variety of microorganisms. including both gram-positive andgramnegative bacteria. Their useful activity can readily be demonstratedby in vitro tests against various organisms in a brain-heart infusionmedium by the usual twofold serial dilution technique. The in vitroactivity of the herein described compounds renders them useful fortopical application in the form of ointments, creams and the like, orfor sterilization purposes, eg, sick-room utensils.

These novel penicillins are also effective antibacterial agents in vivoin animals, including man, not only via the parenteral route ofadministration but also by the oral route of administration.

Obviously. the physician will ultimately determine the dosage which willbe most suitable for a particular individual person. and it will varywith the age, weight and response of the particular patient as well aswith the nature and extent of the symptoms and the pharmacodynamiccharacteristics of the particular agent to be administered. lt willoften be found that when the composition is administered orally, largerquantities of the active ingredient will be required to produce the samelevel as produced by a small quantity administered parenterally.

Having full regard for the foregoing factors it is considered that aneffective daily oral dose of the compounds of the present invention inhumans of approximately -200 mg./kg. per day, with a preferred range ofabout SO-lSU mg/kg. per day in single or divided doses. and a parenteraldose of 2(ll()(l mg/kg. per day. with a preferred range of about 80mg/kg. will effectively alleviate the symptoms of the infection. Thesevalues are illustrative, and there may, of course, be individual caseswhere higher or lower dose ranges are merited.

Many of the penicillin ester compounds of this invention exhibitimproved absorption on oral administra tion over that produced by thecorresponding free acid or alkali metal salt forms. They, therefore,represent convenient and effective dosage forms of (i-[a-(amino)aralkylideneiminolpenicillanic acids.

Further. many of the esters described herein, although inactive or ofrelatively low activity against gram-negative organisms per se are, whenadministered orally to animals. including man, metabolized to the parentacid, which has a wide spectrum of activity against gram-positive andgram-negative bacteria. They thus serve as pro-drug forms of the parentcompounds since they are biologically converted in vivo to saidcompounds. The rate of metabolic conversion of such esters to the parentacid occurs at such a rate as to pro vide an effective and prolongedconcentration of the parent acid in the animal body. In effect, suchesters act as depot sources for the parent acid.

The preferred o-la4amino)aralk lidcneimino} penicillanic acids of thepresent invention are (i-(la-(dimethylaminoJphcnethylidenciminolpenicillanic acid. pivaloyloxymethylester, 6-[ 01- (dimethylamino )phenethylideneimino]penicillanic 6 acid,o-lur-(4morpholinyl)phenethylideneiminolpen cillanic acid.pivaloyoxymethyl ester, 6 {a-(4-methyll-piperazinyl )phenethylideneiminolpenicillanic acid, pivaloyloxymethyl ester, 6-[ a-(4-niethyll piperazinyl )phenethylidcneimino1penicillanic acid,

acetoxymethyl ester and 6-[a-(4-morpholinyl)phene'thylideneimino]penicillanic acid. phenacyl ester.

The antimicrobial spectra of 6-[01-(4-morpholinyl)phenethylideneimino]penicillanic acid, acetoxymethyl esteragainst several bacteria is presented below in Table I. The tests wererun under standardized conditions in which nutrient broth containingvarious concentrations of the test material was seeded with theparticular organism specified, and the minimum concentration (MIC) atwhich growth of each organism failed to occur was observed and recorded.

TABLE I in vitro Data of 6-[a-(4'Morpholinyl)phenethylicleneiminoI-penicillanic acid, acetoxymethyl ester (MIC; mcg/mlJ Organism MICStaphylococcus aureus llllo 0.8 Streptococcus pyogenes U.l)l Pasteurellamultocida fi Hemophilus influenzue 15 Staphylococcus aureus U05 ll] Ery.insidiosa ll.4

TABLE II llA present In vivo Data for (1-[01-(4-methyl-l-piperazinylJphenethylideneiminolpenicillanic acid.acetoxymethyl ester vs. several bacterial infections in mice* E. coli266 Staph. aureus 005 Dose (mg/kg.) PO SO P0 50 IOU 2] l (l 4,1 l U 5/ lll 5/ l (l 50 Zllt) l/lO l/ll) 4/10 TABLE HA In vivo Data for 6'[rx-(l-pipendyllphencthylidcnciminojpenicillanic acid, phenacyl ester vs.bacterial infections in mice* E. coli 26h Staph. aurcus U05 Dose(mg/kg.) PO SQ P0 S0 200 K/lll b/lll l lll Ifll) 5U (t lU .Wlil l/lll(J/lU "PC I oral. St) subcutaneous route of administration Ratio ofsunnorsftoldl mice The novel products of this invention are of value asantibacterial agents and are remarkably effective in treating a numberof infections caused by susceptible gram-negative and gram-positivebacteria in poultry and animals including man. For such purposes, thepure materials or mixtures thereof with other antibiotics can beemployed. They may be administered alone or in combination with apharmaceutical carrier on the basis of the chosen route ofadministration and standard pharmaceutical practice. For example, theymay be administered orally in the form of tablets containing suchexcipients as starch, milk sugar, certain types of clay, etc., or incapsules alone or in admixture with the same or equivalent excipients.They may also be administered orally in the form of elixirs or oralsuspensions which may contain flavoring or coloring agents. or beinjected parenterally, that is, intramuscularly or subcutaneously. Forparenteral administration. they are best used in the form of a sterileaqueous solution which may be either aqueous such as water, isotonicsaline, isotonic dextrose, Ringer's solution, or nonaqueous such asfatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame)and other non-aqueous vehicles which will not interfere with thetherapeutic efficiency of the preparation and are nontoxic in the volumeor proportion used (glycerol, propylene glycol, sorbitol]. Additionally,compositions suitable for extemporaneous preparation of solutions priorto administration may advantageously be made. Such compositions mayinclude liquid diluents, for example, propylene glycol, diethylcarbonate, glycerol, sorbitol, etc.; buffering agents, as well as localanesthetics and inorganic salts to afford desirable pharmacologicalproperties.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE I 6-[a-(Dimethylamino)phenethylideneimino]penicillanic Acid,pivaloyloxymethyl ester hydrochloride A solution of 6-aminopenicillanicacid, pivaloyloxymethyl ester (2.24 g; m moles) in 50 ml, of methylenechloride, cooled in an ice-bath to O-5 C., is treated with L58 g. ofpyridine and phosphorous penta chloride (1.04 g.', 5 m moles). Theresulting reaction mixture is allowed to stir in the cold for l52()minutes and is then washed with water and finally an aqueous sodiumchloride solution. The organic phase, containing the imino chloride, isseparated, dried over sodium sulfate and treated, again at ()-5C., withdimethylamine (450 mg; [0 m moles). After allowing the reaction toproceed at ice-bath temperatures for 30 minutes, the reaction mixture isallowed to stir at room temperature for -30 minutes and is then added towater, The pH is adjusted to 2 with 6 N hydrochloric acid and themethylene chloride layer separated and dried over sodium sulfate.Removal of the organic solvent under reduced pressure provides thehydrochloride salt of the desired product as a yellow foam, 1.6 g. (64%yield; MIC-S. aureus 005: meg/ml).

In a similar manner 6-[a-(dimethylamino)phenethylideneimino]penicillanicacid, methyl ester is pre pared in 569? yield from benzyl penicillinmethyl ester (MIC-S, ill/rem" 005: 200 meg/ml.

EXAMPLE ll Starting with the appropriate penicillin ester, phosphorouspentachloridc and requisite amine, and employing the procedure ofExample I, the following products are synthesized:

EXAMPLE lll o-lwt l-Piperidyl)phcnethylideneiminolpenicillanic acid,pivaloyloxymethyl ester hydrochloride To a solution of benzylpenicillin,pivaloyloxymethyl ester (2.24 g; 5 m moles) in ml. of dry methylenechloride and cooled in an ice bath is added pyridinc 1 .62 mix, 20 mmoles) followed by phosphorous pentachloride (1.04 g; 5 m moles). Thereaction mixture is allowed to stir for minutes and is then added towater. The organic phase is separated. washed with a saturated sodiumchloride solution and. finally. dried over magnesium sulfate.

The methylene chloride solution. containing the intermediateiminochloride is cooled in an ice bath and subsequently treated withpiperidine (0.997 ml.; 10.0 m moles). The reaction mixture is allowed tostir for 1.5 hours in the ice bath and then 2.5 hours at roomtemperature followed by hydrolysis with water and adjustment of the pHto 2 with 6 N hydrochloric acid. The organic phase is separated andextracted consecutively with water, 10% sodium carbonate solution.water. aqueous acid (pH 2). water and finally. a saturated sodiumchloride solution. The methylene chloride layer is then dried overmagnesium sulfate and concentrated to dryness in vacuo. 1.4 g., (55%yield) (MlC S. aureus 005: 0.1 meg/ml.)

In a similar manner are prepared 6-[a-(pyrrolidyl)phenethylideneimino]penicillanic acid. pivaloyoxymethyl ester(55% yield; MIC-S. aureus 005: 12 meg/ml.) and 6-[a-(lpiperidyl)phenethylideneimino]pencillanic acid. phenacyl ester (82%yield. MIC-S. aurens 005: 6 meg/ml.

EXAMPLE IV The procedure of Example 111 is repeated. starting with theappropriate reagents, to provide the following analogs: 6-[a-(l-azacycloheptyl)benzylideneimino]- penicillanic acid. ethyl ester;6-[a-( piperidyl)benzylideneimino]penicillanic acid. phenacyl ester;6-[a-( 1-pyrrolidyl)benzylideneimino]penicil lanic acid. acetoxymethylester; 6-[oz-( l azacyclooctyl)phenethylideneimino]penicillanic acid.

tert-hutyl ester; 6-[a-( l-piperidyl )phenethylideneimino[penicillanicacid, l--( acetoxy)propyl ester; 6-[a-( lpiperidyl)phenpropylideneimino]penicillanic acid. phenacyl ester; 6-[a-(l-azacycloheptyl lphenpropylideneimino]penicillanic acid. l(butyryloxy)ethyl ester; 6-[a-(1-piperidyl)-2'furfurylideneimino]penicillanic acid, n-butyl ester;6-[(! l -azacyclooctyl )-2-furfurylideneimino ]penicillanic acid.l-(acetoxylbutyl ester; 6-[oz-(1-pyrro1idyl)-3-furfurylideneiminolpenicillanic acid. phenacyl ester; 6-{a-( l-azetidinyl )-3-furfurylideneimino]penicillanic acid.l-(propionyloxy)propyl ester; 6-[a-(lpyrrolidyl)-2-furylethylideneiminolpenicillanic acid. ethyl ester;6-[a-( l azacyclooctyl )-2-fury1cthylideneimino]penicillanic acid.phenacyl ester; 6-[a-( piperidyl)-2-furylethylidcneimino]penicillanicacid.

acetoxymethyl ester;6-[a(1azetidyll-2-furylpropylideneiminolpenicillanic acid. isobutylester; fi-ltl- 1-azacyc1oheptyl)-2-furylpropylideneimino]penicillanicacid. phenacyl ester;6-[a-(l-azetidyl)-3-furylpropylideneimino]penicillanic acid. methylester; -[a-( l-azacyclo0ctyl)-3-furylpropylideneimino]- penicillanicacid. pivaloyloxymethyl ester; 6-[01-(pyrrolidyl)-2-thenylideneimino]penicillanic acid. nbutyl ester; 6-a-(piperidyl )-2 thenylideneimino]penicillanic acid. valeryloxymethylester; 6-[0z l-azetidyU-B thenylideneimino]penicillanic acid. phenacylester; 6- [a-( l-piperidyl )-Z-thienylethylideneimino ]penicillanicacid. methyl ester; 6-[a-( l-piperidyl)-2-thienylideneimino]penicillanic acid. phenacyl ester; 6-[a-( l-pyrrolidyl)-3-thienylethylideneimino]penicillanic acid. n-butyl ester; 6-[a-(l-azacylclooctyl)-3- thienylethylideneimino]penicillanic acid,isobutyryloxymethyl ester; 6-[a-(1-azetidyl)-2-thienylpropylideneimino]penicillanic acid. n-propyl ester;6- [a-( l-azacycloheptyl)-3-thienylpropylideneimino]- penicillanic acid.methyl ester; and 6-[a-( l-piperidylj-3-thienylpropylideneimino]penicillanic acid. phenacyl ester.

EXAMPLE V 6-[a-(4-Morpholinyl)phenethylideneimino]penicillanic acid.acetoxymethyl ester To 30 ml. of methylene cloride. cooled in an icebath and under a nitrogen atmosphere. is added benzylpenicillinacetoxymethyl ester (2.0 g.; 4.9 m moles) followed by pyridine (1.59 ml.19.7 m moles) and phosphorous pentachloride (1.025 g; 4.92 m moles). Thereaction mixture is allowed to stir for 30 minutes and is then washedwith water and dried over sodium sulfate.

To the methylene chloride is added morpholine (0.86 ml.-. 9.84 m moles)and the reaction allowed to stir in an ice bath for one hour and then atroom temperature for 1.5 hours. The reaction mixture is then extractedwith 2 X 50 ml. of water, the final wash being adjusted to pH 1 with 2Nhydrochloric acid. The aqueous acid layer is separated, the pH adjustedto 7 with sodium bicarbonate and the product extracted with methylenechloride. The organic phase is separated. dried over sodium sulfate andconcentrated under reduced pressure to provide the product as a yellowfoam. 1.71 g. yield).

In a similar manner are prepared 6-[a-(4-morpholinyl)phenethylideneimino]penicillanic acid. pivaloyloxymethylester yield; MIC-S. aureus 005: 0.1 meg/ml.) and6-[a-(4-morpholinyl)phenethylideneimino]penicillanic acid, phenacylester (80% yield; MIC-S. uureus 005: 0.2 mcg./ml.).

EXAMPLE Vl Starting with the requisite penicillin ester. and condaryamine and following the procedure of Exan"; le V. the followingcongeners are synthesized:

(CH (c11 To a solution of potassium hydroxide (560 mg.; 0.01

mole) in 20 ml. of water and ml. of methanol is EXAMPLE XI added,portionwise, 6-[a- (Diethylamino )benzylideneimino penicillanic acid(375 g.; 0.01 mole) and the mixture is allowed to stir at roomtemperature until almost all the solid has dissolved. The hazy solutionis filtered and the filtrate con- ]5 centrated to a small volume andsubsequently treated A tablet base is prepared by blending the followingingredients in the proportion by weight indicated.

with diethyl ether. The resulting potassium salt is fil- Nizfgnesiun istearatc tered and dried in vacuo.

In a similar manner the pharmaceutically acceptable basic salts ofExample X are prepared. Sufficient6-[a-(dimethylamino)phenethylideneimino1penicillanic acid,pivaloyloxymethyl EXAMAPLE XVI ester is blended into the base to providetablets con- 6 [a (Dimethylamino)phenethy]ideneimino]Penicfl taining 25,100 and 250 mg. of active ingredient. lanic acid pivuloyloxy esterhydmbmmide A methylene chloride solution of 6-10:-

EXAMPLE Xll (dimethylamino)phenethylideneiminolpenicillanic A Suspensionof 6 [a (dimethylamino)phflne acid, pivaloyloxy ester (476 mg; l m mole)is treated thylideneimino]penicil1anic acid sodium salt is prewithSufficient gaseous hydrogen bwmids to Convert pared with the followingcomposition; the free base to the hydrobromide salt. The resultingsolution is concentrated to dryness in vacuo and the residue trituratedwith diethyl ether and filtered.

Pmicim" 3143 I a imil' r manner th roducts ofth r s n i v 70% AqueousSorbitol 71429 g. n 5 e e P e i Glycerin u s ,35 tron are converted totheir pharmaceutically accept- Gum acacia 10'7: solution) 100.00 ml. blSalts Polyvinyl pyrrolidnnc 0.50 g.

Propyl parahydroxybenzoate 0.072 g at IS ClllllTIQd 1S:

Dsnned mike E- l. A compound selected from the group consisting ofpenicillins having the formula: Various sweetening and flavoring agentsmay be added to this suspension, as well as acceptable color ing. Thesuspension contains approximately 25 mg. of 40 1 penicillin compound permilliliter.

(CH c N S CH EXAMAPLE XIII I E311 Capsules containing 25, I00 and 250mg. of active 0 N C0 ingredient are prepared by blending sufficient6-[01-(4- 2 3 methylpiperazinyl)phenethylideneimino]penicillanic' acid,pivaloyloxymethyl ester in the following mixture (proportions given inparts by weight):

wherein:

Ar is selected from the group consisting of phenyl,

furyl and thienyl; n is an integer of from 0 to 2;

Calcium carbonate U 7 5 R and R when considered separately are eachalkyl if; containing from 1 to 5 carbon atoms; Lucrus USP. ,3 R and Rwhen takcn together with the nitrogen 1 atom to which they are attachedform a hcterocv- Magnesium stcaratc 1.0

(.ilC ring of the formula.

EXAMPLE XIV A parenteral form of 6-[a-(4-m0rpholinyl)phcnc- Zthylidcneimino]penicillanic acid, pivaloyloxymcthyl ester sodium salt isprepared by dissolving an intimate Q mixture of thepenicillin compoundand sodium citrate (471 by weight) in sufficient polyethylene glycol 200such that the final concentration of the penicillin comwherein x and areintegers of from I to 3; and Z is sepound is 25 mg. of active ingredientper milliliter. The v lccled from g p Consisting of 2. 5 n resultingsolution is sterilized by filtration and sterilely l WheTEifl 4 isSeleclcd from the g oup n i ing stoppered i i l of hydrogen phcnyl,benzoyl carboalkoxy containing from 2 to 5 carbon atoms and alkyl.alkanoyl and alkylsulfonyl each containing from i to 4 carbon atoms.

R, is selected from the group consisting of hydrogen.

alkyl containing from 1 to 4 carbon atoms, phenacyl andl-alkanoyloxyalkyl wherein said aikanoyl group contains from 2 to 5carbon atoms and said alkyl contains from i to 4 carbon atoms:pharmaceutically acceptable acid addition salts thereof; andpharmaceutically acceptable basic salts thereof wherein R is hydrogen.2. A compound of claim 1 wherein Ar is phenyl, n is l and R and R, areeach alkyl containing from i to 5 carbon atoms.

3. The compound of claim 2 wherein R and R, are each methyl and R is(CH;,) CCO CH 4. The compound of claim 2 wherein R and R are each methyland R is hydrogen.

5. A compound of claim 1 wherein Ar is phenyl, n is l and R, and R takentogether with the nitrogen atom to which they are attached form aheterocyclic ring of the formula:

(Hair New wherein .v and are integers of from l to 3; and Z is selectedfrom the group consisting of CH 0, S and N-R wherein R is selected fromthe group consisting of hydrogen, phenyl. benzoyl. carboalkoxycontaining from 2 to 5 carbon atoms and alkyl, alkanoyl andalkylsulfonyl each containing from 1 to 4 carbon atoms.

6. The compound of claim 5 wherein and are each 2, Z is and R is (CH;,)CCO CH 7. The compound of claim wherein .Y and v are each 2, Z is N-CHand R is (CH ,);.CCO CH 8. The compound of claim 5 wherein X and areeach 2, Z is N-CH and R is CH CO CH 9. The compound of claim 5 whereinand y are each 2, Z is O and R is phenacyll 10. A compound of theformula 1 8 H Q' I l I "f H s 3 10 wherein R and R are each alkyl from 1to 5 carbon atoms and R is H or pivaloyloxymethyl.

11. A compound selected from the group consisting of penicillins havingthe formula:

wherein X is an integer of from 1 to 2; or R and R when taken togethermay be N-morpholino;

R is selected from the group consisting of H and alkanoyloxymethylhaving 5 carbon atoms in the alkanoyl portion; and theirpharmaceutieally acceptable salts.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PENICILLINS HAVINGTHE FORMULA:
 2. A compound of claim 1 wherein Ar is phenyl, n is 1 andR1 and R2 are each alkyl containing from 1 to 5 carbon atoms.
 3. Thecompound of claim 2 wherein R1 and R2 are each methyl and R3 is(CH3)3CCO2CH2-.
 4. The compound of claim 2 wherein R1 and R2 are eachmethyl and R3 is hydrogen.
 5. A compound of claim 1 wherein Ar isphenyl, n is 1 and R1 and R2 taken together with the nitrogen atom towhich they are attached form a heterocyclic ring of the formula:
 6. Thecompound of claim 5 wherein x and y are each 2, Z is 0 and R3 is(CH3)3CCO2CH2-.
 7. The compound of claim 5 wherein x and y are each 2, Zis N-CH3 and R3 is (CH3)3CCO2CH2-.
 8. The compound of claim 5 wherein xand y are each 2, Z is N-CH3 and R3 is CH3CO3CH2-.
 9. The compound ofclaim 5 wherein x and y are each 2, Z is 0 and R3 is phenacyl.
 10. Acompound of the formula
 11. A compound selected from the groupconsisting of penicillins having the formula: